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1.
PLoS Genet ; 8(3): e1002572, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22438824

RESUMEN

Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression.


Asunto(s)
Cerebelo , Proteína GAP-43 , Meduloblastoma , Óxido Nítrico Sintasa de Tipo II/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Transformación Celular Neoplásica , Cerebelo/citología , Cerebelo/crecimiento & desarrollo , Cerebelo/metabolismo , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Ratones Mutantes , Neuronas/citología , Neuronas/metabolismo , Óxido Nítrico , Óxido Nítrico Sintasa de Tipo II/deficiencia , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptores Patched , Receptor Patched-1 , Transducción de Señal , Células Madre/citología , Células Madre/metabolismo
2.
J Neurochem ; 123 Suppl 2: 98-107, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23050647

RESUMEN

Diphenyleneiodonium (DPI), a NADPH oxidase inhibitor, reduces production of reactive oxygen species (ROS) and confers neuroprotection to focal cerebral ischemia. Our objective was to investigate whether the neuroprotective action of DPI extends to averting the immune response. DPI-induced gene changes were analyzed by microarray analysis from rat brains subjected to 90 min of middle cerebral artery occlusion, treated with NaCl (ischemia), dimethylsulfoxide (DMSO), or DMSO and DPI (DPI), and reperfused for 48 h. The genomic expression profile was compared between groups using ingenuity pathway analysis at the pathway and network level. DPI selectively up-regulated 23 genes and down-regulated 75 genes more than twofold compared with both DMSO and ischemia. It significantly suppressed inducible nitric oxide synthase signaling and increased the expression of methionine adenosyltransferasesynthetase 2A and adenosylmethionine decarboxylase 1 genes, which are involved in increasing the production of the antioxidant glutathione. The most significantly affected gene network comprised genes implicated in the inflammatory response with an expression change indicating an overall suppression. Both integrin- and interleukin-17A-signaling pathways were also significantly associated and suppressed. In conclusion, the neuroprotective effects of DPI are mediated not only by suppressing ischemia-triggered oxidative stress but also by limiting leukocyte migration and infiltration.


Asunto(s)
Antiinflamatorios/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Infarto de la Arteria Cerebral Media/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/etiología , Compuestos Onio/uso terapéutico , Análisis de Varianza , Animales , Antiinflamatorios/farmacología , Citocinas/genética , Citocinas/metabolismo , Perfilación de la Expresión Génica , Integrinas/genética , Integrinas/metabolismo , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/prevención & control , Análisis de Secuencia por Matrices de Oligonucleótidos , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
3.
Eur Neurol ; 62(1): 30-9, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19407453

RESUMEN

BACKGROUND/AIMS: Inflammation plays an important role in atherosclerosis and stroke. Acute infections are recognized as trigger factors for ischemic stroke. METHODS: In this whole genome expression profile study of 15 patients and 15 control subjects, we tested the hypothesis that patients with a history of atherothrombotic stroke show enhanced transcription of inflammatory genes in circulating leukocytes. RNA from unstimulated or lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed with Affymetrix U133A GeneChips using a pooling design. Expression of single genes and functional groups of genes was analyzed by global statistical tests. RESULTS: A total of 10,197 probe sets showed positive calls. After correction for multiple testing no single probe set revealed significant differences either without or with LPS stimulation. However, significant global expression differences were found upon LPS stimulation for the group of genes that are involved in cell-cell signaling. CONCLUSION: LPS stimulation of PBMCs, a condition mimicking bacterial infection, induces differential expression of a group of cell-cell signaling genes in patients with previous atherothrombotic stroke. This finding can be caused by genetic differences between both groups, but acquired risk factors, medication and technical factors may also have contributed to the result.


Asunto(s)
Isquemia Encefálica/genética , Expresión Génica , Inflamación/genética , Leucocitos Mononucleares/fisiología , Transducción de Señal/genética , Accidente Cerebrovascular/genética , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/sangre , Femenino , Genoma , Humanos/genética , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Accidente Cerebrovascular/sangre
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